Division of Experimental Oncology 2, Centro di Riferimento Oncologico, National Cancer Institute, Aviano, Italy.
EMBO Mol Med. 2013 May;5(5):707-22. doi: 10.1002/emmm.201201504. Epub 2013 Apr 22.
Stathmin is a p53-target gene, frequently overexpressed in late stages of human cancer progression. Type II High Grade Epithelial Ovarian Carcinomas (HG-EOC) represents the only clear exception to this observation. Here, we show that stathmin expression is necessary for the survival of HG-EOC cells carrying a p53 mutant (p53(MUT) ) gene. At molecular level, stathmin favours the binding and the phosphorylation of p53(MUT) by DNA-PKCS , eventually modulating p53(MUT) stability and transcriptional activity. Inhibition of stathmin or DNA-PKCS impaired p53(MUT) -dependent transcription of several M phase regulators, resulting in M phase failure and EOC cell death, both in vitro and in vivo. In primary human EOC a strong correlation exists between stathmin, DNA-PKCS , p53(MUT) overexpression and its transcriptional targets, further strengthening the relevance of the new pathway here described. Overall our data support the hypothesis that the expression of stathmin and p53 could be useful for the identification of high risk patients that will benefit from a therapy specifically acting on mitotic cancer cells.
Stathmin 是 p53 的靶基因，在人类癌症进展的晚期经常过度表达。II 型高级别上皮性卵巢癌（HG-EOC）是唯一明显的例外。在这里，我们表明，在携带 p53 突变（p53（MUT））基因的 HG-EOC 细胞中，stathmin 的表达对于细胞的存活是必需的。在分子水平上，stathmin 有利于 DNA-PKCS 与 p53（MUT）的结合和磷酸化，最终调节 p53（MUT）的稳定性和转录活性。抑制 stathmin 或 DNA-PKCS 会损害 p53（MUT）依赖性的几个 M 期调节剂的转录，导致 M 期失败和 EOC 细胞死亡，无论是在体外还是体内。在原发性人卵巢癌中，stathmin、DNA-PKCS、p53（MUT）过表达及其转录靶标之间存在很强的相关性，进一步加强了这里描述的新途径的相关性。总的来说，我们的数据支持这样的假设，即 stathmin 和 p53 的表达可以用于鉴定那些将从专门针对有丝分裂癌细胞的治疗中受益的高危患者。
